Society Transactions

The symposium was arranged to evaluate the significance of plasma incompatibility in blood transfusion. Special reference was given to IgA and anti-IgA antibodies since these have been shown to cause serious transfusion reactions. However, there are no generally accepted guidelines for blood banks as to which measures should be taken to prevent such reactions. In addition, it is unclear whether other plasma proteins can be a cause for untoward transfusion reactions. As the first contribution, J. KOISTINEN (Helsinki, Finland) presented some data on the inheritance of selective IgA deficiency. He had taken 35 IgA-deficient blood donors as propositi and studied 180 of their first degree relatives. 13 of them were also found to be IgA deficient which is almost 20 times more than in normal population. Subnormal concentrations of IgA (0.01-0.37 mg/ml) were found in an additional 13 relatives. These figures showed that there was a clustering of IgA deficiency in the families. However, no consistent mode of inheritance was found. In 4 families, the inheritance seemed to be autosomal dominant whereas in 4 other families this seemed to be recessive. As a conclusion, it was suggested that there would be one major gene which would cause a total lack of serum IgA. In addition, there would be modifier genes which would cause IgA deficiency of different degrees when the major gene is absent. S. GUDMUNDSON and 0. JENSSON (Reykjavik, Iceland) had studied the frequency of IgA deficiency in about 2,000 Icelandic blood donors. This amount represented about 1% of the total population of Iceland. Six individuals were detected to be deficient of IgA as determined by immunodiffusion methods. The frequency was well in accordance with earlier reports from other countries. The relatives of these IgA-deficient blood donors were also studied but no clear evidence for a possible single gene inheritance of this situation was found.

As the first contribution, J. KOISTINEN (Helsinki, Finland) presented some data on the inheritance of selective IgA deficiency. He had taken 35 IgA-deficient blood donors as propositi and studied 180 of their first degree relatives. 13 of them were also found to be IgA deficient which is almost 20 times more than in normal population. Subnormal concentrations of IgA (0.01-0.37 mg/ml) were found in an additional 13 relatives. These figures showed that there was a clustering of IgA deficiency in the families. However, no consistent mode of inheritance was found. In 4 families, the inheritance seemed to be autosomal dominant whereas in 4 other families this seemed to be recessive. As a conclusion, it was suggested that there would be one major gene which would cause a total lack of serum IgA. In addition, there would be modifier genes which would cause IgA deficiency of different degrees when the major gene is absent.
S. GUDMUNDSON and 0. JENSSON (Reykjavik, Iceland) had studied the frequency of IgA deficiency in about 2,000 Icelandic blood donors. This amount represented about 1% of the total population of Iceland. Six individuals were detected to be deficient of IgA as determined by immunodiffusion methods. The frequency was well in accordance with earlier reports from other countries. The relatives of these IgA-deficient blood donors were also studied but no clear evidence for a possible single gene inheritance of this situation was found. G. N. VYAS (San Francisco, Calif.) summarized his extensive experience of IgA deficiency and anti-IgA antibodies. He divided the anti-IgA antibodies into three categories: (1) class-specific anti-IgA antibodies in persons lacking total IgA; (2) allotypic antibodies to either of the IgA2 genetic markers, and (3) antibodies with limited specificity in persons having a normal serum level of IgA.
Class-specific anti-IgA antibodies present in high titers (more than 256) provoke serious anaphylactic reactions to transfusions of small volumes of blood and blood products containing IgA. At the University of California, San Francisco, there is a growing opinion of clinicians that sensitizations of individuals known to lack IgA should be prevented by availing IgA-deficient blood from normal blood donors previously selected to form a part of a donor registry. Such registries have been established in several countries (Canada, Denmark, Finland, and the United States). Dr. VYAS noted that a prerequisite for formation of class-specific anti-IgA antibodies is a total lack of IgA as measured by hemagglutination inhibition assay or radioimmunoassay. Thus, persons with even very small amounts of IgA may not be a t risk to form these dangerous antibodies.
Although anti-IgA of limited specificity has been implicated in the anaphylactoid, urticarial, or serum sickness symptoms following blood transfusion, only anti-IgA against the first allotype of human IgA (A2ml) has been clearly shown to be the cause of transfusion reactions in four Caucasian patients. Since there is, so far, no evidence for polymorphism in IgA1, the possibility of antibodies to these hypothetic genetic markers has still to be evaluated. In a case of nonhemolytic transfusion reaction, the presence of antibodies to platelets, leukocytes, IgG, and ,8-lipoprotein antibodies should be carefully investigated and characterized before anti-IgA antibodies with limited specificity are related to the clinical symptoms. Transfusion reactions in Caucasian patients immunized against A2ml can be avoided by transfusion of A2m(-l) blood procured easily from black and oriental blood donors who have a high degree of polymorphism for this genetic marker. E. VAN LOGHEM (Amsterdam, The Netherlands) discussed her results on investigations of class, subclass and allotype specificity of antibodies to IgA. To determine these antibodies, she had coupled isolated IgA myeloma proteins to red cells by the chromic chloride method. For screening of antibodies, she uses cells coated with at least three different IgAl myeloma proteins (as it is likely that allotypes of IgAl exist) and the two IgA2 allotypes. The pattern of agglutination already gives some information as to the specificity of the antibodies. The antibody may be directed against all proteins or either of the subclasses. Also, allotype A2ml o r A2m2 antibodies may be found.
Dr. VAN LOGHEM also described a case of severe transfusion reaction recently investigated at the Netherlands Red Cross Blood Transfusion Service. The patient's serum was found not to contain anti-IgA but it did have anti-Glm(z) antibodies with an extremely high titer of 1:10,000. Anti-Gm antibodies are mostly of the IgM class. In contrast, however, this antibody was shown to be IgG. As antibodies to IgA are in general of IgG class, the conclusion was drawn that the class of the antibody may be more important than the target antigen considering their role in transfusion reactions. It seems that IgG antibodies may cause transfusion reactions whereas IgM antibodies do not.
The next paper by J. KOISTINEN and J. LEIKOLA (Helsinki, Finland) dealt with weak anti-IgA antibodies of limited specificity in patients with mild transfusion reactions, and in multiple transfused patients. At the Finnish Red Cross Blood Transfusion Service, 158 patients with transfusion reactions of different types (mainly fever and urticaria) had been studied. All patients had normal amounts of IgA. Anti-IgA antibodies of limited specificity were observed in 16 of them. In all of these the titer was less than 1:16. Since there was a suspicion that isolated IgA myeloma proteins used as antigen in this study might undergo partial denaturation during the storage in a refrigerator, IgA proteins stored for 8 months were compared with fresh ones. When 36 normal sera were tested, it turned out that none of the sera had antibodies to any of four fresh proteins. On the contrary, most of the sera had antibodies against one of the stored proteins and some of the sera, also against other stored or enzyme-digested proteins. It was concluded that weak anti-IgA antibodies of limited specificity may predominantly be directed against antigenic sites on IgA molecules that are revealed by denaturation or enzymatic digestion. Relationship of these weak antibodies t o clinical symptoms remained unsettled.
L.-A. HANSON and C. WADSWORTH (Gothenburg, Sweden) had studied aggregates of IgG and IgA in commercial 11-globulin preparations, their presence was a consistent finding in these preparations. These aggregates as well as fragments present in the preparations had been characterized and quantitated by a thin-layer gel filtration technique which includes immunodiffusion and immuno-gel filtration. Especially the IgA aggregates were studied in detail. These were shown to be sensitive to reducing agents suggesting that they may be formed by disulfide in their chains. In addition, Fab-and Fc-fragments of both immunoglobulins were found. The degree of aggregation and fragmentation varied widely between the different preparations. The authors pointed out that the fragments and aggregates of IgA may increase the risk of immunization with IgA in certain persons.
W. RUDOWSKI (Warsaw, Poland) was not able to attend the congress but he had sent his contribution in written form immediately after the congress. H e had studied the reactions following plasma transfusions in two patients. The first patient had a large abscess in her left lung and a severe secondary anemia. Two attempts to transfuse blood and plasma resulted in severe reactions with chills, dyspnea, cyanosis, vomiting, and arterial hypotension. Serological investigations revealed a high-titered anti-Gm(a) antibody in the patient's serum. When the patient was transfused with washed erythrocytes, the transfusion went uneventfully. The second patient was a hemophiliac who received 265 packs of cryoprecipitate after an operation. Later, the patient's erythrocytes which were of the blood group A,B, were found to be Coombs-positive, and in an elution test, anti-A and anti-B were found. This showed that large amounts of cryoprecipitate may bring isoantibodies to the patients.
J. RING (Munich, FRG) presented a paper on incompatibility reactions after human serum albumin infusion, which occur in Munich with a frequency of 0.03% among 22,000 infused bottles. Regarding the clinical symptoms, two types of incompatibility reactions were distinguished: immediate reactions with hypotension, tachycardia, and exanthema after the first infusion of albumin (in the most severe case with complete respiratory and cardiac arrest), and late reactions occurring only after some days in patients who had been given large amounts of human serum albumin (1-2 Vday). Skin tests and in vitro lymphocyte transformation experiments suggested that the reactions may have been due to aggregates in the commercial human serum albumin solutions.

Discussion
In the following discussion the moderator pointed out some questions that have often been asked by blood bank medical personnel and that could be discussed in this context (table I). Table I . 1 What is the difference between deficiency and absence of IgA? 2 Should special measures be taken before transfusion of blood products to patients with IgA deficiency'? 3 Should blood donors or recipients be screened for presence of IgA? 4 Should blood banks establish a registry of IgA-deficient blood donors? 5 Are there other reasons for plasma incompatibility besides IgA and anti-IgA? 6 What kind of investigations should be done after a non-hemolytic transfusion reaction?
First, it was discussed whether lymphocytes of IgA deficient persons carry achain marker or not. Dr. VAN LOGHEM had some evidence that the structural a-gene was present in these persons, but a regulatory gene might control the release of IgA to the serum. Dr. HARBOE emphasized the need for careful testing of anti-IgA reagents used for studies like this. If a very low percentage of lymphocytes has been seen to carry IgA on their surface, all possible measures should be taken to rule out the possibility of a false positive immunofluorescence. Dr. KOISTINEN mentioned the possibility of a difference between IgA deficiency and a total lack of IgA and he suggested that in total lack of IgA, the structural genes may also be involved, the person, thus, not being able to produce a-chains. The moderator referred to some preliminary studies by AHO and KOISTINEN, according to which persons with the total lack of IgA may be more susceptible to respiratory infections than persons with very small amounts of IgA in their serum. The latter group was no different from normal controls.
Dr. GREENWALT commented the question of whether blood banks should maintain a registry of IgA-deficient donors. He pointed out that there may be legal barriers against the establishment of such a registry. Could blood donors be tested for IgA deficiency without asking their consent? Would these persons have a higher incidence of diseases, and should a special immunoglobulin be prepared for these persons? He was concerned what to tell the donors, and would it be proper to keep a registry from a moral and ethical point of view.
Dr. KOISTINEN, Dr. HANSON and Dr. VAN LOGHEM were very much in favor for creation of such a registry to provide safe blood transfusion to persons who do not have IgA. Dr. KOISTINEN mentioned that Finnish blood donors had well accepted the idea to keep such a registry.
Dr. HANSON raised a question on the prophylaxis of IgA-deficient persons travelling to hepatitis endemic areas since there had been a report that IgA deficiency might increase the risk of hepatitis. Dr. VYAS replied to part of this question and mentioned that evidence against an increased risk to hepatitis in IgA-deficient persons has been published (Br. med. J. March 29, p. 730, 1975). There was no unequivocal opinion as to whether these persons should be given prophylactic yglobulin in this connection or not.
When the role of the anti-IgA antibodies of limited specificity in blood transfusion reactions was discussed, Dr. VYAS pointed out that when investigating these antibodies, a sufficient number of different myeloma proteins should always be used. He had used a panel of 25 different IgA proteins at the highest, and he recommended that at least 4-6 IgAl proteins, one IgA2 protein which is A2ml-positive and one A2m2-positive protein should be used in the panel. Otherwise some antibodies to a hypothetical y-A1 genetic marker are likely to be missed.
When concluding the symposium, the moderator stressed the point that only a few of the questions in this field can be answered at the present. One of the most important unsettled questions is whether blood recipients should be screened for IgA deficiency. He pointed out the danger of creating a screening routine before one could be sure that the whole process would be worth the time and effort invested to such a program. Once a screening routine is started, it is not very easy to stop it even if the benefit turns out to be questionable.